Viroporins are oligomeric, pore forming, viral proteins that play critical roles in the life cycle of pathogenic viruses. Viroporins like HIV-1 Vpu, Alphavirus 6 K, Influenza M2, HCV p7, and Picornavirus 2B, form discrete aqueous passageways which mediate ion and small molecule transport in infected cells. The alterations in host membrane structures induced by viroporins is essential for key steps in the virus life cycle like entry, replication and egress. Any disruption in viroporin functionality severely compromises viral pathogenesis. The envelope (E) protein encoded by coronaviruses is a viroporin with ion channel activity and has been shown to be crucial for the assembly and pathophysiology of coronaviruses. We used a combination of virtual database screening, molecular docking, all-atom molecular dynamics simulation and MM-PBSA analysis to test four FDA approved drugs - Tretinoin, Mefenamic Acid, Ondansetron and Artemether - as potential inhibitors of ion channels formed by SARS-CoV-2 E protein. Interaction and binding energy analysis showed that electrostatic interactions and polar solvation energy were the major driving forces for binding of the drugs, with Tretinoin being the most promising inhibitor. Tretinoin bound within the lumen of the channel formed by E protein, which is lined by hydrophobic residues like Phe, Val and Ala, indicating its potential for blocking the channel and inhibiting the viroporin functionality of E. In control simulations, tretinoin demonstrated a lower binding energy with a known target as compared to SARS-CoV-2 E protein. This work thus highlights the possibility of exploring Tretinoin as a potential SARS-CoV-2 E protein ion channel blocker and virus assembly inhibitor, which could be an important therapeutic strategy in the treatment for coronaviruses.

Viroporin是一种寡聚的，成孔的病毒蛋白，在病原性病毒的生命周期中起着至关重要的作用。诸如HIV-1 Vpu，Alphavirus 6 K，M2流感病毒，HCV p7和Picornavirus 2B的病毒蛋白形成离散的水通道，介导离子和小分子在感染细胞中的转运。病毒蛋白诱导的宿主膜结构改变对于病毒生命周期中的关键步骤（如进入，复制和流出）至关重要。viroporin功能的任何破坏都会严重损害病毒的发病机理。冠状病毒编码的包膜（E）蛋白是具有离子通道活性的维罗帕林，已被证明对冠状病毒的组装和病理生理至关重要。我们结合使用了虚拟数据库筛选，分子对接，全原子分子动力学模拟和MM-PBSA分析，以测试四种FDA批准的药物-维甲酸，甲芬那酸，恩丹西酮和蒿甲醚-作为SARS-CoV-2 E蛋白形成的离子通道的潜在抑制剂。相互作用和结合能分析表明，静电相互作用和极性溶剂化能是药物结合的主要驱动力，而维甲酸是最有希望的抑制剂。维甲酸结合在E蛋白形成的通道内腔中，该蛋白内衬有疏水残基（如Phe，Val和Ala），表明其可能阻断通道并抑制E的viroporin功能。在对照模拟中，维甲酸显示了较低的结合力与SARS-CoV-2 E蛋白相比具有已知靶标的能量。